Key Points
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Population genetics can be applied to investigate how natural selection has shaped the variability of innate immunity genes in the human population, providing an indispensable complement to immunological as well as clinical and epidemiological genetic approaches. Recent studies have shown that the impact of selection on the different families of innate immune receptors and their downstream signalling molecules varies considerably, helping to delineate the relative functional importance of the corresponding pathways.
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Receptors such as endosomal Toll-like receptors (TLRs) and most NACHT, LRR and pyrin domain-containing proteins (NALPs), adaptors such as myeloid differentiation primary response protein 88 (MYD88) and TIR domain-containing adapter molecule 1 (TRIF), or effector molecules such as a subset of type I interferons (IFNs) and IFNγ have been targeted by strong purifying selection, highlighting the essential and non-redundant nature of the immunological mechanisms involved.
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Other families of innate immunity molecules, such as the RIG-I-like receptors (RLRs), the cell-surface TLRs, and most nucleotide-binding oligomerization domain-containing (NOD)/Ice protease-activating factor (IPAF)/MHC class II transactivator (CIITA) subfamily members of the NOD-like receptor (NLR) family have evolved under much weaker selective constraints, suggesting greater redundancy in the pathways triggered by these molecules.
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Events of positive selection have targeted genetic variation at various innate immunity molecules, such as type III IFNs, attesting to the presence of functional variation at these genes and consequently in the immune responses mediated by them, which has allowed for increased host survival under specific environmental pressures, probably related to pathogen presence.
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Striking differences in selective pressures have been detected in most genes involved in single-gene versus complex diseases, supporting the notion that life-threatening infectious diseases in childhood result mostly from rare single-gene variations, whereas the genetic component of predisposition to secondary infections in adults is more complex.
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Thus, population genetics helps us to differentiate between innate immune genes that have a high degree of redundancy and those that are essential and non-redundant. The identification of essential genes is particularly important for molecules whose functions remain poorly described, as this helps to prioritize genes to be further studied from an immunological standpoint.
Abstract
Innate immunity involves direct interactions between the host and microorganisms, both pathogenic and symbiotic, so natural selection is expected to strongly influence genes involved in these processes. Population genetics investigates the impact of past natural selection events on the genome of present-day human populations, and it complements immunological as well as clinical and epidemiological genetic studies. Recent data show that the impact of selection on the different families of innate immune receptors and their downstream signalling molecules varies considerably. This Review discusses these findings and highlights how they help to delineate the relative functional importance of innate immune pathways, which can range from being essential to being redundant.
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Acknowledgements
We would like to thank M. Albert, L. Barreiro, J.-L. Casanova, G. Eberl, E. Patin and J. Pothlichet for helpful comments and discussions. This work was supported by Institut Pasteur, the Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche (ANR-08-MIEN-009-01), the Fondation pour la Recherche Médicale, and an École Polytechnique Federale de Lausanne-Debiopharm Life Sciences Award to L.Q.-M. The laboratory of L.Q.-M. has received funding from the French Government's Investissement d'Avenir program, Laboratoire d'Excellence “Integrative Biology of Emerging Infectious Diseases” (grant no. ANR-10-LABX-62-IBEID), and from the European Research Council under the European Union's Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement No. 281297. A.G.C. receives funding from the US National Institutes of Health (R01 AI064950).
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Glossary
- Next-generation sequencing
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Non-Sanger-based, high-throughput methods that are able to produce thousands or millions of sequence reads at once. Next-generation sequencing can be used for the direct sequencing of genomes and transcripts, but also to learn more about genome-wide variation of regulatory mechanisms: for example, variation in transcription factor binding sites or epigenetic modifications such as DNA methylation.
- Whole-exome sequencing
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A technology that involves capturing the exonic portion of the genome (roughly 2–3% of the human genome) using microarrays and then applying next-generation sequencing. This approach remains more affordable than whole-genome sequencing and retains the most likely sources of genetic disease risk. This technology is increasingly being used in medical genetics studies.
- Genome-wide association studies
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(GWAS). Unbiased genome-wide screens in which associations between genetic variation and a phenotype or trait of interest are identified by genotyping cases (for example, diseased individuals) and controls (for example, healthy individuals). The dominant technology used so far has been genome-wide single-nucleotide polymorphism arrays.
- Fitness
-
A measure of the capacity of an organism to survive and reproduce.
- Synonymous mutations
-
Substitutions of one nucleotide for another in the DNA sequence of an exon that do not alter the corresponding amino acid sequence. Synonymous mutations that occur outside protein-coding genes are broadly known as silent mutations. Synonymous and silent mutations are often assumed to be neutral.
- Non-synonymous mutations
-
Nucleotide substitutions in an exon that, in contrast to synonymous changes, alter the amino acid sequence of a protein. Depending on how radical the amino acid change is, the impact of a non-synonymous mutation on protein function is variable and subject to natural selection to different extents.
- Single-nucleotide polymorphisms
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(SNPs). Bi-allelic (typically) base-pair substitutions, which are the most common forms of genetic polymorphism.
- International HapMap Project
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The International HapMap Project has built a haplotype map of the human genome and reports the common patterns of human genetic variation based on the results of genotyping analyses. This freely available data set reports information on the allelic frequencies of up to 3 million single-nucleotide polymorphisms distributed throughout the genome, across different human populations.
- 1000 Genomes Project
-
The 1000 Genomes Project aims to provide a large number of complete human genome sequences from individuals from different ethnic backgrounds. The advantage of this project is that it provides information on all forms of DNA polymorphism as well as on low-frequency and rare variants, which are absent in the HapMap Project.
- Complement receptors
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The complement system is a family of serum proteins and cell-surface receptors that participate in innate and adaptive immunity, and is one of the main effector mechanisms of antibody-mediated immunity. They act in concert to mediate inflammation, enhance B and T cell immunity, and regulate self-reactive B cells.
- Ficolins
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A group of humoral proteins that contain a collagen-like domain and a fibrinogen-like domain. They can bind carbohydrate molecules on pathogens, apoptotic and necrotic cells to activate the lectin–complement pathway.
- Collectins
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C-type lectins that have a collagen-like domain. One group of collectins, the secreted lectins, consists of mannose-binding lectin (MBL), bovine conglutinin (BKg) and collectin 43 (CL43) in blood, and the two mucosal-associated proteins surfactant protein A (SPA) and SPD. The other group of collectins consists of the newly discovered non-secreted-type collectin liver 1 (CL-L1) and membrane-type collectin placenta 1 (CL-P1).
- Pentraxins
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Pentraxins constitute a superfamily of evolutionarily conserved proteins characterized by a cyclic multimeric structure and the presence in the carboxyl terminus of a pentraxin domain. They are prototypic components of the humoral arm of innate immunity.
- Lectin–complement pathway
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The lectin–complement pathway involves carbohydrate recognition by pattern-recognition receptors, such as mannose binding lectin (MBL) and ficolins, and the subsequent activation of associated unique enzymes that are known as MBL-associated serine proteases (MASPs). Other complement pathways include the classical-complement pathway and the alternative-complement pathway.
- Defensins
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A class of antimicrobial peptides that have activity against Gram-positive and Gram-negative bacteria, fungi and viruses. Defensins are classified into two main categories on the basis of the position of conserved cysteine and hydrophobic residues and the linkages of disulphide bonds: α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells. A third category, the θ-defensins, arises from the splicing of two α-defensin-related peptides into a circular molecule; at present, these defensins have been detected only in the neutrophils of rhesus macaques.
- Genetic drift
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The random fluctuations in allele frequencies over time that are due to chance alone.
- DEATH domain
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A protein domain that is found in many proteins that are involved in cellular signalling processes, including apoptosis, inflammation and development. This domain mediates protein–protein interactions.
- Expression quantitative trait loci
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(eQTLs). Genomic loci in which genetic variants alter individual differences in quantitative levels of gene expression.
- ENCODE Consortium
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The goal of the Encyclopedia of DNA Elements (ENCODE) Consortium is to systematically map regions of transcription, transcription factor association, chromatin structure and histone modification. In doing so, it provides new insights into the organization and regulation of the human genome and constitutes an expansive resource of functional annotations for biomedical research.
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Quintana-Murci, L., Clark, A. Population genetic tools for dissecting innate immunity in humans. Nat Rev Immunol 13, 280–293 (2013). https://doi.org/10.1038/nri3421
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DOI: https://doi.org/10.1038/nri3421
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